In human patients, lethality from cancer is almost invariably due to the consequences of metastasis. Therefore, understanding the molecular pathways that underlie the emergence and growth of metastasis is of great biological and clinical significance. Our proposed studies of prostate carcinogenesis will investigate the stages of progression to metastatic disease, and will be facilitated by the design and analysis of "next-generation" mouse models of advanced stages of prostate cancer that permit the identification, imaging, and molecular analysis of metastases. In our work, we will address fundamental questions concerning the origin and spread of metastatic disease, including: Do metastatic cells arise early or late in cancer progression? What is the basis for the tissue-selectivity of metastasis? What are the consequences of androgen ablation or surgical prostatectomy for metastasis? Are there metastasis-associated genes that specifically promote or suppress metastatic disease? What is the role of the epithelial-mesenchymal transition in metastasis? Our specific aims are: (1) Detection of metastatic cells in a mouse model of prostate cancer by lineage-marking of prostatic epithelium to examine the time course and tissue distribution of disseminated metastatic cells. (2) Whole-animal non-invasive imaging of metastatic disease through longitudinal studies of prostate cancer growth and metastasis using in vivo imaging techniques. (3) Molecular analysis of metastatic cells and identification of metastasis associated genes by gene expression profiling of isolated metastatic cells for the identification and functional investigation of genes up- and down-regulated in metastatic cancer. (4) Functional analysis of metastasis-associated genes in the prostate epithelium by inducible gene targeting approaches to determine whether candidate genes play a key role in progression to metastasis, with a focus on regulators of the epithelial-mesenchyrnal transition. Our studies should identify the rate-limiting steps in the metastatic cascade, visualize the spread of metastasis in vivo, and provide an entry-point to studying the molecular basis for its tissue-selectivity, all of which should have important implications for prostate cancer treatment.